Project description DEENESFRITPL Tuberculosis: a persistent menace Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), is the leading single infectious cause of death worldwide, claiming more than one million lives per year. Treatment is complicated by long duration, primary treatment failure, disease recurrence, and increasingly-prevalent drug resistance. All of these complications are linked to a phenomenon known as phenotypic tolerance, by which some bacteria within a drug-susceptible population transiently survive exposure to a drug without acquiring heritable resistance mutations. Tolerant cells—called persisters—are thus prime targets for new therapeutics that could improve outcomes in TB, but the mechanisms by which they survive would-be lethal antibiotic exposure remain a mystery. To understand this phenomenon, COMBATTB is uncovering the genetic factors and metabolic pathways that lead to phenotypic tolerance in Mycobacterium tuberculosis. The thorough understanding of these pathways will establish an essential foundation for building better, faster TB drug regimens that could help save countless lives. Show the project objective Hide the project objective Objective Mycobacterium tuberculosis (Mtb) is one of about a dozen bacterial species for which some clinical isolates are now resistant to most or all antibiotics (abx) approved for treatment of the infections they cause. Mechanisms of antimicrobial resistance (AMR) in Mtb deserve study for their potential relevance to AMR in other pathogens; because tuberculosis (TB) is now the leading cause of death from infectious disease; and because drug-resistant TB may be the most prevalent of all drug-resistant bacterial infections. Heritable AMR in Mtb emerges with interruption of treatment, and the long duration of TB treatment provides many opportunities for interruption. Prolonged treatment is necessary because of nonheritable resistance, also called phenotypic tolerance or persistence, defined as the transient tolerance of bacteria in an antibiotic-sensitive population to an antibiotic during exposure to an otherwise lethal concentration of that antibiotic. In contrast to “resisters”, whose AMR is genetically encoded, “persisters” are genetically sensitive bacteria whose phenotypic tolerance allows them to survive for prolonged periods during what would otherwise be rapidly curative treatment. In addition, phenotypic tolerance is likely a source of treatment failure and a major contributor to TB reactivation after apparently effective treatment. The specific aims of this application are to identify genetic determinants that foster phenotypic tolerance in Mtb and decipher at a molecular level the mechanisms by which Mtb enters and maintains a persistent state. Fields of science natural sciencesbiological sciencesmicrobiologybacteriologymedical and health scienceshealth sciencesinfectious diseasesmedical and health sciencesclinical medicinepneumologytuberculosismedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibioticsmedical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2018 - Individual Fellowships Call for proposal H2020-MSCA-IF-2018 See other projects for this call Funding Scheme MSCA-IF-EF-RI - RI – Reintegration panel Coordinator IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE Net EU contribution € 212 933,76 Address South kensington campus exhibition road SW7 2AZ London United Kingdom See on map Region London Inner London — West Westminster Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
